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Reprint requests to: Dwight E. Heron, M.D., F.A.C.R.O., Univer-sity of Pittsburgh Cancer Institute, UPMC Cancer Pavilion, 5150

S. Y. Lais current address is: Department of Head and Neck Sur-gery, University of Texas M. D. Anderson Cancer Center, Houston,TX.

Int. J. Radiation Oncology Biol. Phys., Vol.-, No.-, pp. 18, 2009Copyright 2009 Elsevier Inc.

Printed in the USA. All rights reserved0360-3016/09/$see front matter

doi:10.1016/j.ijrobp.2008.12.075

ARTICLE IN PRESSCentre Avenue, #545, Pittsburgh, PA 15232. Tel: (412) 623-6723;INTRODUCTION

Squamous cell carcinoma of the head and neck (SSCHN) is

the sixth most common malignancy worldwide, with approx-

imately 500,000 cases annually. In the United States, 45,660

new cases and 11,210 deaths were expected in 2007 (1). The

5-year survival rate of 40% for patients with SCCHN in the

United States and other developed countries is comparable

to the 5-year survival rate in the 1970s, despite advances in

detection, surgery, radiation, and chemotherapy (2, 3). Re-

current disease remains a significant problem: nearly 50

60% of these patients will die because of recurrent

locoregional disease (46). Cure rates after recurrence

remain dismal at 16% with single-modality therapy (6).

Chemotherapy has been commonly used for palliation in re-

current disease, with response rates of approximately 30%

and a median survival of 5 to 6 months (7, 8).

Reirradiation of head-and-neck cancers has posed a signif-

icant challenge in the past, given concerns of limited tissue

tolerance (8, 9). Nevertheless, in the setting of recurrent

SCCHN, locoregional disease predominates, and thus the op-

portunity for focused treatment may offer an opportunity for

cure in a subset of patients. Reirradiation has been shown to

produce local control rates of up to 50%, with 5-year survival

of approximately 20% in highly selected cases (6, 913). Un-

fortunately, anticipated tissue complications have been re-

ported as high as 40% with some reirradiation schedulesFax: (412A preli

poster forClinical OPurpose: To evaluate the safety and efficacy of stereotactic body radiotherapy (SBRT) in previously irradiatedpatients with squamous cell carcinoma of the head and neck (SCCHN).Patients and Methods: In this Phase I dose-escalation clinical trial, 25 patients were treated in five dose tiers up to44 Gy, administered in 5 fractions over a 2-week course. Response was assessed according to the Response Eval-uation Criteria in Solid Tumors and [18F]-fluorodeoxyglucose standardized uptake value change on positronemission tomographycomputed tomography (PET-CT).Results: No Grade 3/4 or dose-limiting toxicities occurred. Four patients had Grade 1/2 acute toxicities. Fourobjective responses were observed, for a response rate of 17% (95% confidence interval 2%33%). The maximumduration of response was 4 months. Twelve patients had stable disease. Median time to disease progression was4 months, and median overall survival was 6 months. Self-reported quality of life was not significantly affectedby treatment. Fluorodeoxyglucose PETwas a more sensitive early-measure response to treatment than CT volumechanges.Conclusion: Reirradiation up to 44 Gy using SBRT is well tolerated in the acute setting and warrants furtherevaluation in combination with conventional and targeted therapies. 2009 Elsevier Inc.

Head-and-neck squamous cell carcinoma, Head-and-neck cancer, Stereotactic body radiotherapy, Reirradiation,PET-CT.CLINICAL INVESTIGATION

STEREOTACTIC BODY RADIOTHERACARCINOMAOFTHEHEADANDNECK:

TR

DWIGHT E. HERON, M.D., F.A.C.R.O.,* ROBERT L.REGIANE S. ANDRADE, M.D.,* ERIN L

WILLIAM E. GOODING, M.S.,jj BARTON F. BRANSTJONAS T. JOHNSON, M.D.,y ATHANASSIOS A

AND STEPHEN Y.

Departments of *Radiation Oncology, yOtolaryngology, xRadioMedical Oncology, University of Pi) 647-1161; E-mail: herond2@upmc.eduminary analysis of a portion of this study was presented inm at the 43rd Annual Meeting of the American Society ofncology, June 15, 2007, Chicago, IL.

1FOR RECURRENT SQUAMOUS CELLULTSOFAPHASE I DOSE-ESCALATIONL

RIS, M.D., PH.D.,yMICHALIS KARAMOUZIS, M.D.,z

EEB, B.S.,x STEVEN BURTON, M.D.,*ER, M.D.,yx{ JAMES M. MOUNTZ, M.D., PH.D.,x

RIS, M.D.,z JENNIFER R. GRANDIS, M.D.,y

I, M.D., PH.D.y

, jjBiostatistics, and {Biomedical Informatics, and zDivision ofgh Cancer Institute, Pittsburgh, PAConflict of interest: none.Received May 19, 2008, and in revised form Dec 9, 2008.

Accepted for publication Dec 24, 2008.

ARTICLE IN PRESS(10, 11). These studies have demonstrated the relationship of

dose and volume of reirradiated tissue as the major predictor

for treatment-related complications. There is some evidence

that the soft tissues of the head and neck may tolerate reirra-

diation doses as high as 90% of the original dose if delivered

between 6 weeks and 12 months after initial treatment (14

16). Furthermore, reirradiation with either brachytherapy or

external beam yields comparable long-term survival rates

of 1525% (911).

Stereotactic body radiotherapy (SBRT) is a relatively new

technique that can be applied to deliver high doses of radia-

tion to tumors anywhere in the body with greater precision

when compared with other, more conventional techniques.

This can be accomplished by the CyberKnife Precision Radi-

ation Delivery System (Accuray, Sunnyvale, CA), which of-

fers an attractive alternative for the treatment of patients who

have inoperable or surgically complex tumors or those who

have had prior radiotherapy. The device is an image-guided

stereotactic radiosurgery delivery system that does not

require the application of an invasive head frame for cranial

radiosurgery. Other technical specifications of this system

have been previously reported (17). The integrated imaging

and delivery system has been used to treat extracranial dis-

ease, such as primary and metastatic lung and spine tumors

and prostate cancers, as well as head-and-neck cancers (18,

19). Stereotactic body radiotherapy also offers the ability to

deliver fractionated radiosurgical treatment plans for larger

lesions, minimizing the radiation of adjacent healthy tissues

to potentially decrease the rate of complications. We previ-

ously reported our initial experience using this system, which

resulted in local control rates (20) comparable to those with

conventional techniques. On the basis of these promising ret-

rospective findings in a cohort of patients in whom conven-

tional external beam or intensity-modulated radiotherapy

(IMRT) would have been challenging, we designed a Phase

I dose-escalation trial to evaluate the safety, efficacy, and im-

pact on quality of life of SBRT in patients with recurrent,

inoperable SCCHN.

PATIENTS AND METHODS

Between March 2005 and March 2007, we accrued 31 patients

who had previously undergone radiation treatment for SCCHN

and who re-presented with radiologically measurable, recurrent dis-

ease that was deemed to be unresectable and who had Eastern Co-

operative Oncology Group (ECOG) performance status of 02. In

general, SBRT was selected as the choice for reirradiation when

the treating radiation oncologist deemed full-dose re-treatment

(i.e., >60 Gy) with either three-dimensional or IMRT as challengingbecause of proximity to the spinal cord or other critical structures. In

some instances consideration of patient tolerance of a protracted

course of treatment was important, because SBRT treatment deliv-

ered over the course of 10 days was more readily accepted by pa-

tients than a re-treatment course of 6 to 7 weeks. Patients who

received at least 1 fraction of treatment were considered eligible

for toxicity assessment. This Phase I clinical trial (University of

Pittsburgh Cancer Institute no. 04-144) was approved by the Univer-

2 I. J. Radiation Oncology d Biology d Physicssity of Pittsburgh Institutional Review Board, and informed consent

was obtained from each patient.All patients were evaluated with physical examination and cross-

sectional CT imaging. The majority of patients had a combined

[18F]-fluorodeoxyglucose (FDG) positron emission tomography

computed tomography (PET-CT) scan no more than 4 weeks before

enrollment. The Revised University of Washington Quality of Life

Questionnaire (21) was administered to each patient before treat-

ment and 1 month after treatment. This is a self-reported appraisal

of quality of life in which 12 domain-specific items are scored by

the patient from 0 (worst) to 100 (best). These 12 domains are aver-

aged to yield a composite score for each patient.Patients were treated with the CyberKnife Robotic Radiosurgical

System (Accuray). An individualized treatment plan was developed

for each patient according to the clinical and radiographic findings.

The gross target volumewas defined by the radiographic and clinical

areas of known gross disease, augmented by PET-CT when avail-

able. Critical structures were also contoured for exclusion from

treatment. All patients were treated to the 80% isodose line, which

was intended to cover >90% of the target volume. Radiation dose

was administered in 5 fractions over a 2-week period. No chemo-

therapy was given concurrently with SBRT. The dose to all critical

structures other than the spinal cord was not routinely available in

most patients because many of them were initially treated at outside

institutions. In general, critical structure constraints were as follows:

spinal cord maximum dose: #8 Gy; larynx: # 20 Gy; mandible:#20 Gy; parotid: variable; brainstem:#8 Gy; oral cavity: variable.Dose escalation was dictated by a nonparametric adaptive plan

that estimates a dose-limiting toxicity (DLT) rate of 20% for the

maximally tolerated dose. Up to 10 patients were to be treated at

the highest dose (44 Gy) per protocol. Acute toxicity was defined

as occurring during the course of treatment and extending until

3 months after treatment. Chronic toxicity was defined as those

events occurring thereafter. To assess the acute toxicity of each

dose tier, a 4 -week observation period was necessary before esca-

lation to the subsequent tier was allowed.Response assessment was conducted by the head-and-neck radi-

ologist (B.F.B.) and a head-and-neck surgeon (J.R.G.). Response

Evaluation Criteria in Solid Tumors (RECIST) were used for the as-

sessment of response at approximately 30 days for patients with CT

only (n = 4) and 4560 days for those with PET-CT. Tumor size wasbased on CT measurements. Response to PET was based on stan-

dardized uptake values (SUV).The maximum SUV value (SUVmax) in the tumor region defined

by the tumor target volume region of interest (ROI) was measured

both before and after therapy by a radiation oncologist (R.S.A.)

and nuclear medicine radiologists (E.D. and J.M.M.). In addition,

owing to relatively high background SUV values in normal head-

and-neck regions, a background correction SUV (SUVbkg) in an

adjacent but uninvolved neck region ROI was obtained. Fluoro-

deoxyglucose uptake attributable to tumor (SUVtum) was corrected

for background by subtracting SUVbkg from SUVmax. Response

was assessed by comparison between pre- and posttreatment PET

scans according to the criteria proposed by the European Organiza-

tion for Research and Treatment of Cancer (EORTC) PET group

(22). Using this method, we obtained background corrected ratios

of SUVmax in the tumor region before (SUVpre) and after (SUV-

post) therapy to obtain the percentage SUV change in the tumor

as the ratio defined as SUVpost/SUVpre.For PET studies, we categorized the treatment response as pro-

gressive metabolic disease (PMD), stable metabolic disease

(SMD), partial metabolic response (PMR), and complete metabolic

response by grouping the patients percentage SUV change as estab-

Volume-, Number-, 2009lished by the 1999 EORTC recommendations (22). Progressive

metabolic disease is defined as an SUV increase of $25% or new

RESULTS

Patient characteristicsPatient characteristics are outlined in Table 1. Of the 31 (30

male, 1 female) enrolled patients, 25 (81%) completed their

prescribed treatment in 5 equal fractions over a 2-week pe-

riod and were evaluable for response or toxicity. Two

patients died before disease response assessment (one myo-

cardial infarction and one decline in performance status).

Six patients were not evaluable for response for the following

reasons: inability to lay supine for duration of treatment (n =2), patient refusal (n = 2), and unrelated comorbidity (n = 2).

therapy was 13 months (range, 594 months).

Table 1. Patient characteristics

Age (y), median (range) 63 (3586)GenderMale 24Female 1

Primary siteNasopharynx 1Oropharynx 6Larynx 10Oral cavity 7Unknown 1

Tumor volume(cm3), median (range)

44.8 (4.2217)

SBRT for recurrent SCCHN d D. E. HERON et al. 3

ARTICLE IN PRESSFDG-avid areas; SMD is defined as an SUV increase of

Objective response

3 months with a maximum of 4 months.

Table 3. Patient responses by dose tier

Dose (Gy)

Response 25 32 36 40 44 Total

Complete response 1 0 1* 0 0 2Partial response 1* 0 1* 1 2 5Stable disease 0 3 0 3 6 12Progressive disease 0 0 0 2 2 4Not evaluable 1 0 1 0 0 2

* Responses not confirmed.

4 I. J. Radiation Oncology d Biology d Physics

ARTICLE IN PRESSTumor size changes and metabolic response to SBRTPatient SBRT responses were classified by CT volume

changes according to RECIST and by PET metabolic change

according to the EORTC recommendations (Table 4).

Twelve patients had SD by RECIST, but 7 of these patients

showed improvement on PET (PMR), with 2 cases having

had a complete (100%) or near-complete (>90%) resolution

of FDG uptake. However, 2 patients with SD by RECIST

showed PMD on PET. Five patients with PD by RECIST

also showed PMD on PET. Figure 1AD depicts an example

of PET and PET-CT response to SBRT.

In cases of PR, agreement between CT and PET were

mixed. In 2 patients with PR showing a modest decrease inOf the 25 patients completing their therapy, 2 died before

radiographic staging, and the remaining 23 were assessed for

clinical response (Table 3). Among the 23 patients who were

evaluable for response, 1 had a complete response (CR) and 3

had partial response (PR) meeting RECIST definitions, for

a response rate of 17.4% (95% confidence interval [CI]

2%33%). Twelve patients had stable disease (SD), and 4

had progressive disease (PD). Two patients with objective re-

sponses (1 CR, 1 PR) died before a confirmatory scan could

be obtained and therefore did not qualify as response by RE-

CIST. Response rate was independent of dose (p = 0.209) andinitial treated volume (p = 0.306) (Table 2). Median durationof response, including the unconfirmed responses, wasTable 4. Tumor response to SBRT by RECIST and PET

Response RECIST PET

CR/CMR 2 2PR/PMR 5 10SD/SMD 9 1PD/PMD 5 6Total 23 19

Abbreviations:SBRT= stereotactic body radiotherapy;RECIST=Response Evaluation Criteria in Solid Tumors; PET = positronemission tomography; CR = complete response; CMR = completemetabolic response; PR = partial response; PMR = partial metabolicresponse; SD = stable disease; SMD = stable metabolic disease;PD = progression of disease; PMD = partial metabolic disease.the tumor size, PET demonstrated an increase in FDG uptake

suggesting PMD, but these patients ultimately were con-

firmed as PD on subsequent follow-up. Another case consid-

ered PR by CT but SMD by PET with a mild FDG response

(3%) ultimately was confirmed to have persistent disease

with a modest FDG change (38%) on a later PET-CT study.

Additionally, in 2 cases considered PD by CT, a decrease was

observed in the FDG uptake. One patient had a 45% reduc-

tion in FDG avidity, and the subsequent PET-CT study

showed a substantial increase, confirming progression

(PMD). In the other case, a 64% decrease in the FDG was

seen, but this patient developed a new primary lung cancer

and died during treatment without confirmation of disease

response in the neck.

Quality of lifeThe Revised University of Washington Quality of Life

Questionnaire was administered to 24 patients before

SBRT, of whom 16 completed the survey after treatment.

Among those completing the questionnaire at both times,

overall quality of life declined. The median decrease in the

composite score was 10 (two-tailed signed rank test, p =0.0831). Quality of life at baseline and quality-of-life change

with treatment were unrelated to performance status (Krus-

kal-Wallis p = 0.604 and 0.648, respectively). Major self-reported issues affecting 3050% of patients at baseline

were speech, swallowing, pain, and saliva. These issues

persisted after treatment.

Patterns of failurePatterns of failure are important criteria in assessing the

efficacy of treatment, given the highly conformal nature of

SBRT and the concern about marginal misses. Treatment

volumes were created without additional dosimetric margins

(i.e., no planning target volume). Nonetheless, much like ourretrospective experience (20), patients rarely failed exclu-

sively at the boundary of the SBRT field. Rather, all failures

were either entirely within the radiation portal, outside the

field, or a combination of both. Although the prognosis is of-

ten poor in patients with recurrent disease, focused therapy

can offer significant local control and palliation. On the basis

of the tumor treated with SBRT, the observed treatment re-

sponse (radiologic and metabolic: CR + PR + SD) was

76% (19 of 25). However, we were unable to establish a rela-

tionship between dose, tumor size, and probability of local

control in this patient cohort.

SurvivalOf the 23 patients with known disease status, 12 patients

had documented progression, 9 patients died without docu-

mented disease progression, and 2 patients are alive without

progression. The median time to progression was 4 months

(95% CI 46 months; Fig. 2A). The probability of 6-month

disease-free survival was 0.31 (95% CI 0.130.51).

Twenty-three of 25 patients have died. The median overall

survival was 6 months (95% CI 58 months). Two patients

Volume-, Number-, 2009with SD remain alive at 14 and 18.5 months after treatment

cancers, locoregional recurrences remain a significant prob-

Fig. 1. Positron emission tomographycomputed tomography (PET-CT) scans of recurrent squamous cell carcinoma ofmetas

SBRT for recurrent SCCHN d D. E. HERON et al. 5

ARTICLE IN PRESSlem in 5060% of patients. Many of those patients dying

from disease have local or regional disease as the sole site

of failure (2325). Although salvage surgery remains the

mainstay of therapy for the majority of patients with recurrent

disease, some are poor surgical candidates or have unresect-and were treated on dose tier 5 (44 Gy). Figure 2B shows

a Kaplan-Meier plot of overall survival with confidence

bands. Figure 3 shows the SBRT plan for the patient depicted

in Fig. 1. Note the steep dose gradient between the gross tar-

get volume and the adjacent spinal cord.

DISCUSSION

Despite major advances in the treatment of head-and-neck

the head and neck: primary (A, C) and cervical (B, D)body radiotherapy.able disease. For the vast majority of patients with recurrent

head-and-neck cancer, surgical resection remains the single

most important factor in effecting durable salvage. However,

Fig. 2. Progression-free and overall survival. (A) Kaplan-Meicompleting stereotactic body radiotherapy with known diseasintervals. (B) Kaplan-Meier curve depicts overall survival foThe dashed lines represent 95% confidence intervals. Tick marin patients deemed to be unresectable or medically inopera-

ble, other options must be explored. Chemotherapy may pro-

vide meaningful palliation, but few patients achieve durable

control even with multiagent regimens. Although reirradia-

tion has been advocated as a possible modality for salvaging

patients with recurrent disease confined to the head and neck,

it has been discouraged because of concerns over normal tis-

sue complications, including soft-tissue necrosis, fibrosis,

transverse myelopathy/myelitis, and radionecrosis of the

mandible and cartilage of the head and neck.

The introduction of highly conformal techniques such as

three-dimensional conformal radiotherapy (3D-CRT) and

IMRT has renewed interest in aggressive reirradiation pro-

grams. The primary tenets of these programs have been to

limit the size of the radiation field, reduce the re-treatment

tatic disease before (A, B) and after (C, D) stereotacticdoses, and adopt altered fractionation schemes to minimize

toxicity. It is now generally accepted that cytotoxic doses

in excess of 60 Gy are necessary to optimize salvage

er curve depicts progression-free survival for 23 patientse status. The dashed lines represent the 95% confidencer 25 patients completing stereotactic body radiotherapy.ks represent censoring times/events.

for

ARTICLE IN PRESSFig. 3. Representative stereotactic body radiotherapy plangross tumor volume (GTV) and spinal cord.

6 I. J. Radiation Oncology d Biology d Physicsprobability in patients with recurrent SCCHN (12). Reirra-

diation alone has been shown to result in up to 50% local con-

trol, although significant debilitating risks including fatal

toxicity have been reported (26). Approaches that combine

therapeutic modalities, such as reirradiation and concomitant

chemotherapy, have shown a better chance for long-term

cure, with median survival rates of 1535% for 2 years, al-

though at the expense of increased toxicities and a significant

risk for toxic death (510%) (3, 13, 27, 28). More recently,

approaches using 3D-CRT and IMRT with or without hyper-

fractionation have been reported (2931). Response rates

have been reported as high as 6070% but were associated

with significant Grade 3 and 4 toxicities ranging from 10%

to 40%. However, in many patients, the close proximity of re-

current disease to critical structures, such as the mandible,

spinal cord, and parotid glands, has often made reirradiation

virtually impossible, particularly if the tissue tolerance has

already been exceeded and the time to recurrence interval

is short, usually

REN

7. HongWK, Schaefer S, Issell B, et al. A prospective randomized

rent squamous cell carcinoma of the head and neck. Cancer1983;52:206210.

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21. Weymuller EA Jr., Alsarraf R, Yueh B, et al. Analysis of the

CHN

ARTICLE IN PRESSuation of cisplatin plus fluorouracil versus cisplatin plus pacli-taxel in advanced head and neck cancer (E1395): Anintergroup trial of the Eastern Cooperative Oncology Group.J Clin Oncol 2005;23:35623567.

9. Emami B, Bignardi M, Spector GJ, et al. Reirradiation ofrecurrent head and neck cancers. Laryngoscope 1987;97:8588.

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11. Stevens KR Jr., Britsch A,MossWT. High-dose reirradiation ofhead and neck cancer with curative intent. Int J Radiat OncolBiol Phys 1994;29:687698.

12. Langer CJ, Harris J, Horwitz EM, et al. Phase II study of low-dose paclitaxel and cisplatin in combination with split-courseconcomitant twice-daily reirradiation in recurrent squamouscell carcinoma of the head and neck: Results of Radiation Ther-apy Oncology Group Protocol 9911. J Clin Oncol 2007;25:48004805.13. Spencer SA, Harris J, Wheeler RH, et al. Final report of RTOG9610, a multi-institutional trial of reirradiation and chemother-performance characteristics of the University of WashingtonQuality of Life instrument and its modification (UW-QOL-R).Arch Otolaryngol Head Neck Surg 2001;127:489493.

22. Young H, Baum R, Cremerius U, et al. Measurement of clinicaland subclinical tumour response using [18F]-fluorodeoxy-glucose and positron emission tomography: review and1999 EORTC recommendations. European Organization forResearch and Treatment of Cancer (EORTC) PET Study Group.Eur J Cancer 1999;35:17731782.

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response in previously treated patients, in whom scar tissue

may obscure response evaluation. Our data show good agree-

ment between PET and CT for the assessment of CR and PD.

However, 7 of 12 cases of SD by CT scan showed marked

partial metabolic response on PET. Additionally, 2 cases of

PR by CT scan that initially showed an increase in FDG up-

take were ultimately were confirmed as PD on subsequent

follow-up. These data suggest that FDG-PET is a more sen-

sitive surrogate early biomarker of beneficial response to

treatment than CT imaging alone. Although a standard

method to measure metabolic change in the assessment of

therapeutic response remains to be established, the additional

information provided by PET might provide more reliable

indicators of treatment response (41).

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SBRT for recurrent SCCONCLUSIONS

The present study represents the first prospective, Phase I

clinical trial of SBRT reirradiation in head-and-neck cancer.

Prior studies were retrospective or combined patients with

different cancers (20, 42, 43). We did not reach an MTD,

and we did not appreciate late toxicities in our patients; how-

ever, we had a relatively short follow-up period. Stereotactic

body radiotherapy seems to be feasible, well-tolerated, and

a potential alternative to surgery or external beam radiation.

Stereotactic body radiotherapy may be a more convenient

and effective form of reirradiation given the relatively short

time required for delivery of the scheduled treatment frac-

tions. On the basis of the results of this trial, we have initiated

a Phase II clinical trial incorporating concurrent cetuximab

with SBRT.

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8 I. J. Radiation Oncology d Biology d Physics Volume-, Number-, 2009

ARTICLE IN PRESS

Stereotactic Body Radiotherapy for Recurrent Squamous Cell Carcinoma of the Head and Neck: Results of a Phase I Dose-Escalation TrialIntroductionPatients and MethodsResultsPatient characteristicsDose escalation and toxicity assessmentObjective responseTumor size changes and metabolic response to SBRTQuality of lifePatterns of failureSurvival

DiscussionConclusionsReferences